Researchers Investigating Sex-Specific Differences in Age-Related Macular Degeneration

UB ophthalmology researchers have received a $2.2 million grant from the National Institute on Aging of the National Institutes of Health to study sex-specific mechanisms for AMD. The goal is to identify novel sex-specific biological mechanisms to lay the groundwork for development of therapies that would be targeted to men or women

“AMD is a chronic neurological condition and there’s no cure and no way to prevent it,” says Margaret M. DeAngelis, MS, PhD, principal investigator and Ira G. Ross and Elizabeth Olmsted Ross Endowed Chair and professor of ophthalmology in the Jacobs School of Medicine and Biomedical Sciences. Because most people don’t exhibit symptoms early in the disease, she says it’s difficult to detect the disease in its early and intermediate stages. For that reason, most AMD studies have focused on the late stages.

“We want to stop progression at an early stage,” says DeAngelis, who also has an appointment in the Department of Biochemistry. “It has been published that women get the worst form of the disease, known as wet AMD, and that it progresses faster in women than men.” Wet AMD can cause vision loss suddenly, sometimes as quickly as overnight.

The UB team’s hypothesis is based on preliminary data it gathered studying intermediate and advanced forms of AMD in well-characterized human donor eyes. The donor eyes are from the unique human donor eye repository in the DeAngelis lab, which she and her colleagues have been curating since 2012 and which provides a key advantage.

“Like other chronic progressive neurological diseases, one of the challenges facing AMD researchers is the fact that there are no animal models of the disease because animals don’t get AMD,” DeAngelis says.

This is because the tissues affected by AMD are unique to the human eye. “Our repository, the first of its kind, gives us direct access to the tissue affected by the disease and we use some of the same imaging techniques used in the clinic on living patients.”

She stresses that the repository would not be possible without the generosity of patients willing to be organ donors and the scientists and clinicians who work to rapidly process and rigorously phenotype the donor eyes according to a standardized published protocol. In this manner, she says, the eyes have the greatest translational impact when they are used for research.

There is increasing evidence that dysfunction in the epigenetics — changes to the expression of DNA without changing the actual DNA sequence — that is associated with chronic neurodegenerative diseases of aging may be more prevalent in women. 

And the UB team’s published and preliminary data suggest the sex differences in AMD may originate in some dysfunction that occurs in the epigenetic interplay or “crosstalk” observed between the nuclear and mitochondrial genomes in the macula from the donor eyes from the biorepository.

Their plan is to leverage their already annotated and well-characterized sex- and age-matched donors with and without different types of AMD and to use a systems biology approach, harnessing a variety of techniques to characterize the interplay between these genomes in the macula.

Researchers will also look at the question of susceptibility and who is more likely to develop AMD. The team has data showing, for example, that there are DNA differences — or “variants” — in the mitochondrial genomes of people with AMD. This suggests that some mitochondrial DNA variants may make people more susceptible to AMD.

“Two significant papers we published in Cell Genomics and Cells on our donor eye repository demonstrated how AMD gene expression changes are specific to the macula (as opposed to the periphery) in the retinal pigment epithelium,” DeAngelis says, “and were able to validate this work in two distinctly separate sets of our donor eye data. The new research will build upon this work."

“Our ultimate goal is to design appropriate preventive or therapeutic targets to restore vision or stop progression,” notes DeAngelis.

Other members of the team include Jesse Slone, PhD, assistant professor in the Department of Pediatrics and co-principal investigator; Treefa Shwani, PhD, postdoctoral associate in the Department of Ophthalmology; and co-investigator Jonathan E. Bard, PhD, research assistant professor, Department of Biochemistry, all in the Jacobs School.